1-substituted-2-thio-1h-1,4-benzodiazepines

ABSTRACT

Disclosed herein are 1-substituted-2-thio-1H-1,4-benzodiazepines which are useful anti-anxiety agents, anti-convulsants, skeletal muscle relaxants and sedative-hypnotic agents.

States Patent] 1 @lelnman Dec 24,1974

[ llSUBSTITUTED-Z-THIO-IH-l,4-

BENZODIAZEPINES Primary Examinerl-lenry R. Jiles .7 Assistant Examiner-Robert T. Bond [75] Inventor. Martln Stelnman, Llvmgston, NJ. AttOmeLAgeM, or Firm Bruce M Eisen; Stephen B [73] 'Assignee: Schering Corporation, Bloomfield, Coan 22 Filed: Sept. 14, 1972 21 Appl. No.: 289,023 57 ABSTRACT [52] US. Cl ...260/243 R, 260/239 BD, Disclosed herein are l-SubStituted-2-thi0-lH-l,4-

. 260/2393 D, 424/244, 424/246 benzodiazepines which are useful anti-anxiety agents, [51] 11m. [In C07d 53/06 anti-convulsams, Skeletal muscle relaxants and Seda- [58] Field of Search 260/239 ED, 243 R fi -hypnotic agents.

[56] References Cited 9 Claims N0 Drawings UNITED STATES PATENTS 3,678,036 7/1972 Archer et al. 260/239 BD cyclopropylmethyl or l-SUBSTITUTED-Z-THIO-lH-l,4- BENZODIAZEPINES wherein X is halogen, trifluoromethyl or nitro; R is lower alkyl, polyfluorolower alkyl, phenyl-loweralkyl,

wherein m is or.1 and R and R are each hydrogen or lower alkyl; R is hydrogen, lower alkyl, hydroxy or lower alkanoyloxy; R is lower alkyl or I wherein n is 0 or 1 and R and R are each hydrogen or lower alkyl; Y is hydrogen, halogen, trifluoromethyl, nitro, hydroxy, lower alkyl orlower alkoxy, and the 4- N-oxides and the pharmaceutically acceptable acid addition salts thereof.

As used herein, the term lower alkyl refers to both straight and branched-chain hydrocarbon radicals having up to six carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like. Phenyllower alkyl can be illustrated by phenethyl and benzyl. Lower alkoxy" includes ether radicals wherein the lower alkyl moiety is as defined for lower alkyl above, such as, for example, methoxy, ethoxy, propoxy and the like. Lower alkanoyloxy includes those .esters containing the acyl radicals of alkanoic acids having up to six carbon atoms such, as'acetyl, propionyl, butyryl, valeryl, hexanoyl and the branched-chainisomers thereof. The term halogen as used herein comprehends all four halogens. In the preferred embodiment of this invention X is chloro.

The term polyfluoro-lower alkyl refers to lower alkylradicals substituted with more than one fluoro radical and includes such moieties as 2,2,2-

trifluoroethyl, trifluoromethyl, 2,2,3,3,3-pentafluoropropyl and the like. In a preferred embodiment of this invention the polyfluoro-lower alkyl moiety has two alpha hydrogen atoms, i.e., R Cl-l -wherein R, is polyfluoroalkyl. Most preferably, R, is trifluoromethyl, i.e., the l-(2,2,2-trifluoroethyl) species.

Pharmaceutically acceptable acid addition salts are well known. Such salts include those formed in the conventional manner with both inorganic and organic acids such as hydrochloric acid, hydrobromic, nitric acid, sulfuric acid, acetic acid, formic acid, succinic acid, maleic acid, p-toluenesulfonic acid and the like.

The compounds of formula I can be prepared by the selective reaction of the corresponding benzodiazepin- I 2-thione with about a stoichiometric amount of lithium aluminum hydride under controlled conditions. The order of addition should be inverse, i.e., the LiAll-l, is added to the benzodiazepin-Z-thione. Further, the addition should be effected at a reduced temperature, i.e., less than about 10 C and typically at 0 C. The reaction can be depicted as follows:

+ LiAlHi (I) wherein X, R R and Y are as previously defined. A suitable inertorganic solvent is employed such as tetrahydrofuran, dioxane, diethylether, benzene or the like. The b'enzodiazepin-Z-thione starting materials may be prepared according to the teachings of Belgian Pat. No.

wherein X, R,, R R and Y'areas previously defined. The Z-hydroxy or 2,3-oxy-benzodiazepine starting material may be prepared according to the teachings of Belgian Pat. No. 742,124.

The following examples illustrate the preparation of representative compounds of this invention.

EXAMPLE 1 7-Chloro-2,3-Dihydro-1-(B,{3,B-Trifluoroethyl)-2- Thioethyl-S-Phenyl-ll-l-l,4-Benzodiazepine Dissolve 1.5 g. of 7-chloro-l-(B,B,B-trifluoroethyl)- 2,3,4,5-tetrahydro--phenyl-2,5-oxy-l H-1 ,4- benzodiazepine in ml. of ethanethiol. Cover the solution and allow it to stand at room temperature for 3 days. Evaporate the solution under a stream of nitrogen. Dissolve the solid residue in a small amount of benzene-ethyl acetate (10:1) and chromatograph on 150 g. of silica gel. Obtain the product of this example upon recrystallization from aqueous ethanol, m.p. 110-1l 1C.

Similarly, one can prepare other compounds of this invention by substituting the corresponding 2,3-oxy or 2-hydroxy-benzodiazepine to produce the desired 1- substituted-2-thioalkyl-2,3-dihydro-5-aryl-11-1-1 ,4- benzodiazepine, as for example:

7-chlorol -dimethylamino-2-thioethyl-2,3-dihydro- 5-(o-fluorophenyl)-1H-1,4-benzodiazepine; 7- trifluoromethyl- 1 -ethyl-2-thioethyl-2 ,3-dihydro-3- methyl-5-(p-iodophenyl)-1H-1,4-benzodiazepine; 7-

nitrol -trifluoromethyl-2-thioethyl-2,3-dihydro-5-(ptolyl)- 1 11-1 ,4-benzodiazepine; 7-chloro-l-(2,2,3,3,3- pentafluoropropyl)-2-thioethyl-2,3-dihydro-5-phenyl- 1H-1,4-benzodiazepine; 7-bromo-l-(1,2,2,2- tetrafluoroethyl)-2-thioethyl-2,3-dihydro-3-methyl-5- (o-chlorophenyl)-1H-1,4-benzodiazepine, and 7- fluoro-l-phenethyl-2-thioethyl-2,3-dihydro-5-(mnitrophenyl)-lH-l,4-benzodiazepine.

EXAMPLE 2 7-Chloro-5-Phenyll -(B,B,B-Trifluoroethyl)-2,3 ,4,5- Tetrahydro-2,5-Thio-l ,4-Benzodiazepine Cool a solution of 3.68 g. of 7-chloro-2,3-dihydro-5- phenyl-1-(B,B,B-trifluoroethyl)-1l-l-l ,4-benzodiazepin- 2-thione in 75 ml. of dry tetrahydrofuran to 0C. To the solution, slowly add 0.38 g. of lithium aluminum hydride. After complete addition, stir the mixture for 5 minutes and then quench with wet ether. Filter the mixture, dry with sodium sulfate and evaporate. Recrystallize the residue from methylene chloride-hexane to yield the compound of this example, m.p. 163-168C.

EXAMPLE 3 7-Chlorol -Methyl-5-Phenyl-2,3 ,4,5-Tetrahydro-2,5 Thiol H-l ,4-Benzodiazepine Dissolve 5 g. of 7-chloro-l,3-dihydro-l-methyl-5- phenyl-ZH-l,4-benzodiazepin-2-thione in 125 ml. of dry tetrahydrofuran. Cool the solution in an ice-salt water bath and add 0.634 g. of lithium aluminum hydride. After 5 minutes quench the reaction with water. Filter the mixture, dry over sodium sulfate and evaporate to yield the crude compound of this example, which is then recrystallized from methylene chloride, m.p. 160-l63C (dec.).

The compounds of this invention exert such selective effects on the mammalian central nervous system as to be particularly useful as sedative-hypnotics, anticonvulsants, muscle relaxants and anti-anxiety agents.

Based upon standard laboratory investigative procedures, such as the Antagonism of Pentylene Tetrazole, Everett and Richard, J. Pharm. and Exp. Ther., Vol. 81, pg. 402 (1944); Antagonism of Maximal Electro- Shock-Induced Seizures in Mice, Synard, EA. et al., J. Pharm. and Exp. Ther., Vol. 106, pg. 319 (1952); An-

tagonism of Foot-Shock lnduced Fighting in Mice, Tedeschi, et al., J. Pharm. and Exp. Ther., Vol. 125, pg. 28 (1959); Taming Activity in Monkeys, Randall Diseases of the Nervous System, Vol. 21, pg. 7 (1960); System Activity and Acute Toxicity, lrwin, Science, 136, pg. 123 (1967), it is indicated that the compounds of this invention, when administered to man within the dosage range of about 0.5 to 3 mg./kg. of body weight per day, produce the hereinabove described beneficial pharmacological effects. These dosage regimen are preferably administered orally in divided doses.

The compounds of this invention may be administered alone or combined with other medicaments. In any event, a suitable pharmaceutically acceptable carrier is generally employed. A carrier is selected taking account of the intended route of administration, the physical properties of the compounds, and standard pharmaceutical practice. It should not react chemically with the compound to be administered. The compositions of this invention are preferably administered orally, although parenteral administration is also contemplated. The preparations containing the active ingredients of this invention may be in the form of tablets, capsules, syrups, elixirs, suspensions and the like.

In the formulations of pharmaceutical preparations there can be employed such pharmaceutically acceptable diluents, as for example, water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils and gums. The following examples show typical tablet and capsule formulations incorporating a compound of this invention.

TABLET FORMULATIONS 1. Formula and Method of Manufacture for 7-chloro-l- (B,B,B-trifluoroethyl)-2,3-dihydro-S-( o-fluorophenyl)- 111-1,4-benzodiazepin-2-thione.

Coated Tablets: mg/core 7-Chloro-1-(B, B, B-trifluoroethyU-L thioethyl-2,3,-dihydro-5-(o-fluoro- I phenyl)-lH-l,4benzodiazepine 25 Lactose. USP 41 Dicalcium Phosphate 40 Sodium Lauryl Sulfate 1O Polyvinylpyrrolidone 10 Water ml/l000 cores Corn Starch 20 Dry mg/corc Sodium Lauryl Sulfate 1 2 Magnesium Stearate 2 Tablet Weight 150 Procedure The 7-chloro-1-(B,B,B-trifluoroethyl)-2,3-dihydro-2- thioethyl-S-(o-fluorophenyl)-1H-l,4-benzodiazepine is mixed with the lactose, dicalcium phosphate, and sodium lauryl sulfate. The above mixture is screened through a No. 60 screen and granulated with an aqueous solution containing polyvinylpyrrolidone. Add additional water, if necessary, to bring powders to a pasty mass. Add corn starch and continue mixing until uniform granules are formed. Pass through a No. 10 screen, tray and dry in oven at C for 12-14 hours. Reduce dried granulation through a No. 16 screen, add sodium lauryl sulfate and magnesium sulfate, mix and compress into desired shape on a tablet machine. Coating The above cores are treated with a lacquer and dusted with talc to prevent moisture-absorption. Subcoat layers are added 'to round out the core. A sufficient number of lacquer sub-coats and smoothing coats are applied to completely round out and smooth the tablet. Color coats are applied until desired shade is obtained. After drying, the coated tablets are polished to give the tablets an even gloss. ll. Capsule Formulations:

Formula: mglcapsule 7-Chloro-l-(B, B, B-trifluoroethyl)-2.3,- dihydro-2-thioethyl-5-(o-fluorophenyl)- l5 lH- l ,4,-benzodiazepine 25 Sodium Lauryl Sulfate Lactose I29 Magnesium Stearate 76 Procedure Mix together 7-chloro-l-(B, B,B-trifluoroethyl)-2,3- dihydro-2-thioethyl-5-(o-fluorophenyl)- 1 PM ,4- benzodiazepine, sodium lauryl sulfate and lactose. Pass through a No. 80 screen. Add magnesium stearate, mix and encapsulate into the proper size two-piece. gelatin capsule.

lII. Suppository Formula: mg/2 gs.

7-Chlorn-l-(B, [3, fi-trifluoroethyl)-2,3- dihydro-2thioethyl-5-(o'fluorophenynlH'lA-benzodiazepine, micronized S0 2 gms.

Theobroma Oil, Pharm. Grade'to make l. A l-substituted-2-thio-lH-l,4-benzodiazepine selected from the group represented by formula I:

and formula Ilz' wherein X is halogen, trifluoro'methyl or nitro; R, is

lower alkyl, polyfluoro-lower alkyl or phenyl-lower alkyl; R is hydrogen or lower alkyl R is lower alkyl or Ru CH CH (CH) N 2 n I l where n is 0 or 1 and R and R are each hydrogen or lower alkyl; Y is hydrogen, halogen or lower alkyl; and the 4-N-oxides and the pharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim ll represented by the formula:

wherein'X is halogen, trifluoromethyl or nitro; R, is

lower alkyl, polyfluoro-lower alkyl or phenyl-lower alkyl; R is hydrogen or lower alkyl; Y is hydrogen, halogen or lower alkyl; and the 4-N-oxides and the pharmaceutically acceptable acid addition salts thereof.

3. A compound according to claim 2 wherein X is chloro.

4. A compound according to claim 2 wherein R is polyfluoro-lower alkyl.

5. A compound according to claim 4 wherein X is chloro.

6. A compound according to claim ll represented by the formula:

wherein X is halogen, trifluoromethyl or nitro; R is lower alkyl, polyfluoro-lower alkyl or phenyl-lower alkyl; R is hydrogen or lower alkyl; R is lower alkyl or wherein X is halogen, trifluoromethyl or nitro; R, is -cu,c1n cII1)n-N lower alkyl, polyfluoro-lower alkyl, or phenyl-lower al- R7 kyl; R is hydrogen or lower alkyl; Y is hydrogen, halogen, or lower alkyl; and the 4-N-oxides and pharmaceu- Where n f l and and R1 are each hydrogen or 5 tically acceptable acid addition salts thereof; comprislower alkyl Y ls'hydmgenhalogenioflower alkyliand ing adding lithium aluminum hydride to an inert orthe 4'N'oxldes and the pharmaceuucauy acceptable ganic solvent containing an approximately stoichiometacid addition Salts thereof; I ric amount ofa benzodiazepin-Z-thione of the formula:

7. A compound according to claim 6 wherein X is chloro.

8. A compound according to claim 7 wherein R is S polyfluoro-lower alkyl. N R 9. A process for the preparation of a compound of 2 the formula:

x H R; H l5 C=N l I I Y /N Rq i s 0 Y X \H C-N 2O wherein X,Y,R, and R are as previously defined, said adding beingconducted at a temperature less than Y 10C. 

1. A 1-SUBSTITUTED-2-THIO-(H-1,4-BENZODIAZEPINE SELECTED FROM THE GROUP REPRESENTED BY FORMULA I:
 2. A compound according to claim 1 represented by the formula:
 3. A compound according to claim 2 wherein X is chloro.
 4. A compound according to claim 2 wherein R1 is polyfluoro-lower alkyl.
 5. A compound according to claim 4 wherein X is chloro.
 6. A compound according to claim 1 represented by the formula:
 7. A compound according to claim 6 wherein X is chloro.
 8. A compound according to claim 7 wherein R1 is polyfluoro-lower alkyl.
 9. A process for the preparation of a compound of the formula: 